The present invention concerns chemically modified forms of epidermal growth factor (EGF) in which the EGF is modified by acylation. The invention also relates to pharmaceutical compositions containing acylated EGF which have increased biological stability and resistance to proteolytic degradation.
Human EGF (also known as urogastrone) is a 53 amino acid polypeptide growth factor that has mitogenic activity for different types of cells, including epithelial and mesenchymal cells. Variants of the human EGF polypeptide have been reported, such as the 52 amino acid gamma-urogastrone. EGF has been reported to be useful in increasing the rate of wound healing as a result of its mitogenic activity. EGF has also been reported as being useful for treating gastric ulcers, cerebral ischemia and psoriasis. A review of EGF is provided by Carpenter et al., in "Epidermal Growth Factor, Its Receptor and Related Proteins," Experimental Cell Research, 164: 1-10 (1986).
The topical or oral therapeutic administration of proteins and peptides is generally hampered because of rapid proteolytic degradation and low absorption from the application sites. EGF is currently used topically to treat wounds, including burns, donor site wounds, and ulcers. EGF also has applications in the treatment of disease conditions such as gastric ulcers and ischemia and reperfusion injuries. The delivery of EGF to patients either parenterally with implanted devices, topically or orally has not been as successful as anticipated. It is believed that this may be a result of loss of biological activity or enzymatic degradation of the EGF molecule. To date, efforts to develop dosage forms for mucosal (e.g., nasal or buccal) or oral delivery have been discouraged specifically because of either low absorption and/or the anticipated inactivation by proteolytic enzymes. Also, for indications in which aqueous solutions of EGF were the preferred dosage form, the practical shelf life of such formulations was questionable.
A limited number of reports on the efficacy of EGF for treating peptic ulcer formation and the healing of chronic gastric ulcers support the protective and curative effects of EGF in these applications. However, the full pharmacological potential of EGF in these applications could not be achieved even when the drug was administered intravenously. Limited success has been reported when EGF is administered in exceptionally large oral doses. As mentioned above, this could be explained in part because of the results of proteolytic degradation and/or low absorption of EGF from the respective dosage forms and/or poorly targeting dosage forms for the duodenal mucosa.
It is also believed that EGF in topical dosage forms are prone to proteolytic degradation by wound proteinases or proteinases from contaminating wound microflora. For wound healing applications, topical dosage forms containing a less proteolytically susceptible EGF will have a prolonged therapeutic efficacy.